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Pioneer and repressive functions of p63 during embryonic ectoderm specification [ChIP-Seq]

ABSTRACT: The transcription factor p63 is a master regulator of ectoderm development essential for epidermal specification. Although previous studies have highlighted the role of p63 triggering the epidermal transcriptomic program, its precise mechanism of target gene regulation in the complex context of a developing embryo remains poorly understood. Here, we used zebrafish embryos to analyze in vivo how p63 regulates the expression of its target genes during development. We generated tp63-knock-out mutants that recapitulate human phenotypes and show down-regulated epidermal gene expression. Following p63-binding dynamics during development, we found two distinct functions clearly separated in space and time. During early development, p63 binds enhancers associated to neural genes, where it limits Sox3 binding and reduces the expression of these neural genes. Indeed, we show that p63 and Sox3 are co-expressed in the neural plate border. Later in development, p63 binds enhancers associated to epidermal genes and promotes their expression, acting as a pioneer factor, as it binds to non-accessible chromatin and is required for its opening. Therefore, our results suggest that p63 is an important regulator of cell fate decisions during ectoderm specification, promoting the epidermal fate and inhibiting the neural program.

ORGANISM(S): Danio rerio

PROVIDER: GSE123057 | GEO | 2019/06/06

REPOSITORIES: GEO

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Pioneer and repressive functions of p63 during embryonic ectoderm specification [ATAC-seq]

Project description:The transcription factor p63 is a master regulator of ectoderm development essential for epidermal specification. Although previous studies have highlighted the role of p63 triggering the epidermal transcriptomic program, its precise mechanism of target gene regulation in the complex context of a developing embryo remains poorly understood. Here, we used zebrafish embryos to analyze in vivo how p63 regulates the expression of its target genes during development. We generated tp63-knock-out mutants that recapitulate human phenotypes and show down-regulated epidermal gene expression. Following p63-binding dynamics during development, we found two distinct functions clearly separated in space and time. During early development, p63 binds enhancers associated to neural genes, where it limits Sox3 binding and reduces the expression of these neural genes. Indeed, we show that p63 and Sox3 are co-expressed in the neural plate border. Later in development, p63 binds enhancers associated to epidermal genes and promotes their expression, acting as a pioneer factor, as it binds to non-accessible chromatin and is required for its opening. Therefore, our results suggest that p63 is an important regulator of cell fate decisions during ectoderm specification, promoting the epidermal fate and inhibiting the neural program.

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Project description:During primary neurulation, the separation of a single-layered ectodermal sheet into the surface ectoderm (SE) and neural tube specifies SE and neural ectoderm (NE) cell fates. The mechanisms underlying fate specification in conjunction with neural tube closure are poorly understood. Here, by comparing expression profiles between SE and NE lineages, we observed that uncommitted progenitor cells, expressing stem cell markers, are present in the neural plate border/neural fold prior to neural tube closure. To identify what type of signaling pathways and transcriptional factors are involved in the fate specification between SE and NE cells during neurulation.

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Mutant p63 disrupts the key specification switch from the multipotent cell state to stratified epithelia during epithelial differentiation/in ectodermal dysplasia disorders

Project description:Transcription factor p63 is a key regulator of stratified epithelia. In humans mutations in p63 are associated with developmental disorders that manifest defects in stratified epithelia including the epidermis. We established an epidermal commitment model using human pluripotent stem cells (PSCs) and characterized differentiation defects of PSCs carrying p63 mutations. Transcriptome analyses revealed distinct phases of epidermal commitment, multipotent simple epithelial, basal stratified epithelial and mature epidermal fates. Differentiation defects of p63 mutant PSCs occurred during the specification switch from the simple epithelium to the basal stratified epithelial fate. Single-cell transcriptome and pseudotime analyses identified enhanced mesodermal signatures associated with the deviated commitment route of p63 mutant PSCs. Repressing mesodermal differentiation improved epidermal commitment of PSCs. Our study demonstrate that p63 is required for specification of stratified epithelia but not sufficient for epidermal maturation. It provides insights into disease mechanisms underlying defects of stratified epithelia caused by p63 mutations.

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Ectoderm specification of H1 human embryonic stem cells

Project description:In recent years, several studies have shed light into the processes that regulate epidermal specification and homeostasis. We previously showed that a broad-spectrum γ–secretase inhibitor DAPT promoted early keratinocyte specification in human embryonic stem cells triggered to undergo ectoderm specification. Here, we show that DAPT accelerates human embryonic stem cell differentiation and induces expression of the ectoderm protein AP2. Furthermore, we utilize RNA sequencing to identify several candidate regulators of ectoderm specification including those involved in epithelial and epidermal development in human embryonic stem cells. Genes associated with transcriptional regulation and growth factor activity are significantly enriched upon DAPT treatment during specification of human embryonic stem cells to the ectoderm lineage. The human ectoderm cell signature identified in this study contains several genes expressed in ectodermal and epithelial tissues. Importantly, these genes are also associated with skin disorders and ectodermal defects, providing a platform for understanding the biology of human epidermal keratinocyte development under diseased and homeostatic conditions. 6 samples were analyzed, 3 replicates of ETOH treated H1 HESCs and 3 replicates of DAPT treated H1 HESCs

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Ectoderm specification of H1 human embryonic stem cells

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Pioneer and repressive functions of p63 during embryonic ectoderm specification

Project description:Pioneer and repressive functions of p63 during embryonic ectoderm specification

| PRJNA507423 | ENA

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Transcription factor p63 bookmarks genomic loci in epithelial cells and regulates a subset of target genes during epidermal differentiation through dynamic enhancers (RNA-Seq)

Project description:Tightly controlled gene expression orchestrated by the transcription factor p63 during epithelial differentiation is important for development of epithelial-related structures such as epidermis, limb and craniofacial regions. How p63 regulates spatial and temporal expression of its target genes during these developmental processes is however not yet clear. By epigenomics profiling in stem cells established from one of these epithelial structures, the epidermis, we provide a global map of p63-bound regulatory elements that are categorized as single enhancers and clustered enhancers during epidermal differentiation. Transcriptomics analysis shows dynamic gene expression patterns during epidermal differentiation that correlates with the activity of p63-bound enhancers rather than with p63 binding itself. Only a subset of p63-bound enhancers is active in epidermal stem cells, and inactive p63-bound enhancers appear to function in gene regulation during the development of other epithelial tissues. Our data suggest a paradigm that p63 bookmarks genomic loci during the commitment of the epithelial lineage and regulates gene expression in different epithelial tissues through tissue-specific active enhancers. The catalogue of differentially expressed epidermal genes including non-coding RNAs and epithelial enhancers reported here provides a rich resource for studies of epithelial development and related diseases. Comparison of gene expression at different stages of keratinocyte differentiation

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